Hepatitis
B therapy is limited by the development of drug resistant virus. Resistance to
lamivudine (Epivir-HBV) can emerge
rapidly when used as monotherapy, but other antiviral agents may be less likely
to promote resistance.
Various
presentations at the recent 57th Annual Meeting of the American Association for
the Study of Liver Diseases (AASLD) in Boston covered the long-term use and emergence
of resistance to the nucleoside analog entecavir
(Baraclude).
Study
1
In
one presentation, T. Chang and colleagues presented 3-year data on the efficacy
and safety of entecavir in an international study.
The
researchers previously determined in pivotal study ETV-022 that entecavir (0.5
mg/day) was superior to lamivudine (100 mg/day) with regard to virological, histological,
and biochemical end-points at Week 48 in nucleoside-naive HBeAg positive chronic
hepatitis B patients. In the second year of therapy, patients receiving entecavir
continued to benefit in terms of HBV DNA reduction, ALT normalization, and HBeAg
seroconversion.
Eligible
patients who achieved virological response (defined as HBV DNA < 0.7 MEq/mLby
bDNA) during Year 2 were offered the opportunity to continue receiving open-label
entecavir in a rollover study (ETV-901). Of the 243 subjects who entered the second
year of therapy, 198 achieved a virological response at Week 96; of these, 119
received entecavir for at least 1 additional year in ETV-901.
Results
Most patients who continued therapy were male (80%) and Asian (68%); the mean
age was 36 years.
At Week 144, 90% of entecavir-treated patients continued to have undetectable
HBV DNA (< 300 copies/mL).
80% experienced ALT normalization (? 1 x ULN).
33% experienced HBeAg loss during the third year of therapy.
16% experienced HBeAg seroconversion during Year 3.
Adverse events (AEs) were generally mild to moderate, and included:
In
conclusion, the researchers wrote, "HBeAg(+) chronic hepatitis B patients
who achieved virologic response after 2 years of entecavir therapy in ETV-022
maintained virologic suppression and ALT normalization during the third year of
therapy in ETV-901, with continued HBeAg loss and seroconversion."
Study
2
Another
study, by R. Colonno and colleagues, looked at developed of entecavir resistance
over 3 years of therapy. According to the researchers, entecavir resistance requires
pre-existing lamivudine-resistance mutations plus additional substitutions at
RT positions T184, S202, and/or M250.
This
study included both nucleoside-naive HBeAg positive and negative patients starting
entecavir as first-line therapy, and treatment-experienced patients who switched
to entecavir from failing lamivudine therapy (defined as HBV DNA rebound >
1 log over nadir).
Results
Among 152 nucleoside-naive subjects without pre-existing lamivudine-resistance
mutations treated during Year 3, 94% maintained or achieved undetectable HBV DNA
(< 300 copies/mL).
Among 673 total nucleoside-naive patients treated with entecavir for 1-3 years,
only 2 experienced virological rebound related to development of entecavir-resistance.
Among 85 lamivudine-refractory patients treated during Year 3, 40% maintained
or achieved undetectable HBV DNA.
13 lamivudine-refractory patients (15%) experience virological rebound; 10 of
the 11 rebounding patients whose virus was analyzed showed evidence of entecavir-resistance
mutations.
Overall, virological rebound related to entecavir resistance in lamivudine-refractory
patients was observed at rates of:
- 1% during Year 1; - 9% during Year
2; - 15% during Year 3.
7% of subjects with entecavir-resistance mutations nevertheless achieved undetectable
HBV DNA with continued entecavir therapy.
In
conclusion, the researchers wrote, "Entecavir continues to demonstrate a
high genetic barrier to resistance amongst nucleoside treatment-naive patients
as shown by the Year 3 results. Among the lamivudine-refractory patients, [40]%
achieved undetectable HBV DNA levels, while an increasing number of patients experienced
virologic rebounds in Year 3 due to pre-existing or emerging entecavir resistance."
Since
entecavir resistance is less likely to develop among patients without pre-existing
lamivudine resistance mutations, the authors added, "The resistance profile
over 3 years in nucleoside-naive patients strongly supports the use entecavir
as a first-line therapy for chronic HBV infection."
"Despite
the fact that the hepatitis B virus is constantly changing, [entecavir] creates
a high barrier to resistance development in nucleoside-naive patients, as demonstrated
by the less than 1% resistance rate through 3 years," said Colonno, vice
president for virology drug discovery at Bristol-Myers Squibb.
Another
study presented by R. Jardi and colleagues, however, found that a proportion of
HBV isolates carried entecavir-resistance mutations even in patients who had never
received previous treatment with nucleoside analogs, and that entecavir-resistance
mutations can emerge during lamivudine monotherapy.
11/10/06
References
T
Chang, T Chao, S Kaymakoglu, and others. Entecavir Maintained Virologic Suppression
Through 3 Years of Treatment in Antiviral-Naive HBeAg(+) Patients (ETV 022/901).
57th AASLD. October 27-31, 2006. Boston, MA. Abstract 109.
R
Colonno, R Rose, K Pokornowski, and others. At Three Years Shows High Barrier
To Resistance Is Maintained In Entecavir-treated Nucleoside Naive Patients While
Resistance Emergence Increases Over Time In Lamivudine Refractory Patients. 57th
AASLD. Abstract 110.
R
Jardi, F Rodriguez-Frias, M Buti, and others. Mutations at HBV-Polymerase Gene
Associated with Entecavir Drug Resistance in Patients Not Undergoing Entecavir
Therapy. 57th AASLD. Abstract 966.
Most patients who continued therapy were male (80%) and Asian (68%); the mean
age was 36 years.
